Triglyceride-enriched low density lipoproteins (LDL) accumulate in the plasma of cholestasis patients. Our goals are to examine parameters relating to the clearance TG-enriched lipoproteins in both cholestatic humans and the rat model of human cholestasis and to investigate secretion by the liver and intestine of TG-rich lipoproteins in the obstructed rat in order to elucidate the pathogenesis of hypertriglyceridemia. The proposed studies should give a comprehensive insight not only into the cause of hypertriglyceridemia of cholestasis, but aid also in our understanding of normal lipoprotein metabolism through the study of the perturbations in metabolism which are reversible with relief of obstruction. The specific aims of this proposal are: 1) To characterize the apo C-II/ apo C-III composition of cholestatic lipoproteins in humans before and after relief of obstruction and in obstructed rats; 2) To determine whether apo C-II-containing cholestatic lipoproteins activate LPL normally; 3) To examine the kinetics of TG turnover in the cholestatic rat model for abnormalities in clearance and/or hepatic secretion; 4) To determine if hepatic TG secretion in the cholestatic rat is elevated by the Triton WR 1339 method, 5) To examine the kinetics of disappearance of hepatic apo B isoforms in cholestatic rat plasma and the secretion of the apo B isoforms by the obstructed, perfused liver, and 6) To examine the effects of bile duct obstruction on intestinal lipoprotein production and composition in rats. The long-term objective of these studies is to better understand the control of lipoprotein metabolism in normal humans and the abnormalities in metabolism which lead to the hypertriglyceridemia of cholestasis. This is of importance in understanding the pathogenesis of other liver diseases characterized by accumulation of abnormal lipoproteins, as well as other familial disorders of lipoprotein metabolism.